There presently exist a lack of methodology for killing specific or target cells within a population of cells. Current methods for doing this, such as chemotherapy and radiation therapy are not specific. Moreover, the side effects associated with chemotherapy and radiation therapy are problematic. Immunotoxin therapy is presently being developed to increase the specificity of chemical agents.
As a class, immunotoxins are hybrid compounds designed to kill specific cells while leaving non-target cells intact. Immunotoxins are formed by chemically linking a potent cell toxin to an antibody which is directed against a target cell component. The antibody moiety provides the specificity of the compound while the cell toxicity is a function of the toxin component.
The efficacy of the immunotoxin is dependent on the nature of its components. Monoclonal antibodies against determinants found only, or in much greater numbers, on target cells are used because of their superior specificity and ease of obtaining large amounts of material. The toxins used are generally found in nature as hetero-dimers themselves.
Ricin is one of a number of plant proteins which, in minute quantities, exhibits considerable toxicity toward eukaryotic cells. Ricin is composed of two glycoprotein chains covalently linked via a single disulfide bond. The A chain of ricin, having an apparent molecular weight of about 30,000, is responsible for the expression of toxicity, and acts enzymatically upon the 60S ribosomal subunit leading to irreversible abrogation of protein syntheses. Ricin B chain, having an apparent molecular weight of about 32,000, functions as a lectin with specificity for galactose and serves to bind the toxin to the plasma membrane. The B chain binds to surface determinants found on virtually all cells. Apart from the binding activity, the B chain also functions in the delivery of A chains to the cytosol.
Immunotoxins made of holotoxins, i.e., containing both A and B subunits are potent cytocidal agents. However, the presence of the B subunit with its nonspecific binding nature, results in high levels of non-target cell death. Nevertheless, immunotoxins made of A subunits only are not potent cytotoxins, because they lack the delivery function associated with the B subunits.
A number of U.S. patents directed to the field of immunotoxins are known, including U.S. Pat. No. 4,664,911 to Uhr et al which is directed to immunotoxin conjugates employing toxin B chain moieties; and U.S. Pat. No. 4,582,703 to Jansen et al which is directed to cytotoxic medicaments formed from the association of at least one immunotoxin and chloroquin.
U.S. Patents which are directed to, or otherwise discuss, the use of immunopotentiators include U.S. Pat. No. 4,911,912 to Casellas et al and U.S. Pat. No. 4,749,566 to Casellas et al, each of which contain a discussion of immunopotentiators, and U.S. Pat. No. 4,490,362 to Shionoya et al which is directed to an immunopotentiator which comprises the B chain of ricin as an active ingredient.
There exists a need for a potentiator which potentiates the specific cytotoxicity of immunotoxins which are made of holotoxins.